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  • Author or Editor: Samuel K. Kulp x
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Objective—To determine whether exposure of canine cancer cells to histone deacetylase (HDAC) inhibitors S(+)-N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)benzamide (OSU-HDAC42) or suberoylanilide hydroxamic acid (SAHA) results in increased histone acetylation and decreased cell viability and whether any changes in viability involve induction of apoptosis or alterations in progression of the cell cycle.

Sample Population—9 canine cancer cell lines.

Procedures—Cells from 9 canine cancer cell lines were treated with dimethyl sulfoxide vehicle, OSU-HDAC42, or SAHA, then assays of cell viability were performed. Histone acetylation was assessed by use of western blot analysis. Apoptosis was assessed via ELISA to detect fragmentation of cytoplasmic nucleosomal DNA and western blot analysis to detect cleavage of caspase 3. Cell cycle analysis was performed by use of propidium iodide staining and flow cytometry.

Results—Concentrations of OSU-HDAC42 and SAHA required to achieve 50% inhibition of cell viability (IC50) were reached in cells of 6 and 4 canine cancer cell lines, respectively, and ranged from approximately 0.4 to 1.3μM for OSU-HDAC42 and 0.6 to 4.8μM for SAHA. Cells from T-cell lymphoma, mast cell tumor, osteosarcoma, and histiocytic sarcoma lines were most sensitive to HDAC inhibition, with IC50s of < 1μM for OSU-HDAC42 and < 5μM for SAHA. Induction of apoptosis was indicated via cleavage of caspase 3 and increases in cytoplasmic nucleosomes and the subG1 cell population.

Conclusions and Clinical Relevance—Micromolar concentrations of HDAC inhibitors OSU-HDAC42 and SAHA induced histone acetylation, cytotoxicity, and apoptosis in canine cancer cells. In general, OSU-HDAC42 was more potent than SAHA.

Full access
in American Journal of Veterinary Research


Objective—To evaluate in vitro biological activity of gemcitabine, alone and in combination with Pamidronate or carboplatin, against canine osteosarcoma (OSA) cell lines.

Sample Population—In vitro cultures of OSA cell lines OSA8, OSA16, OSA32, and OSA36.

Procedures—Cell lines were treated with gemcitabine alone or in combination with pamidronate or carboplatin. Cell viability was assessed with the water soluble tetrazolium-1 (WST-1) assay, cell cycle distribution was evaluated by means of propidium iodide staining, and apoptosis was assessed by measuring caspase-3/7 activity. Synergy was quantified by use of combination index (CI) analysis.

Results—For all of the cell lines, treatment with gemcitabine induced growth inhibition, cell cycle arrest, and apoptosis. No synergistic or additive activity was identified when OSA cell lines were treated with gemcitabine in combination with pamidronate. However, when OSA cell lines were treated with gemcitabine in combination with carboplatin, a significant decrease in cell viability was observed, compared with treatment with carboplatin alone, and the drug combination was determined to be synergistic on the basis of results of CI analysis. For 3 of the 4 cell lines, this activity was greater when cells were treated with carboplatin prior to gemcitabine rather than with gemcitabine prior to carboplatin.

Conclusions and Clinical Relevance—Gemcitabine exhibited biological activity against canine OSA cell lines in vitro, and a combination of gemcitabine and carboplatin exhibited synergistic activity at biologically relevant concentrations. Findings support future clinical trials of gemcitabine alone or in combination with carboplatin for the treatment of dogs with OSA.

Full access
in American Journal of Veterinary Research